tbuckley/cabot-search huggingface dataset:
Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study
Authors: David J Pinato, Juan Aguilar-Company, Daniela Ferrante, Georgina Hanbury, Mark Bower, Ramon Salazar, Oriol Mirallas, Anna Sureda, Andrea Plaja, Marc Cucurull, Ricard Mesia, Sarah Townsend, Amanda Jackson, Alessia Dalla Pria, Thomas Newsom-Davis, Jasmine Handford, Ailsa Sita-Lumsden, Eleanor Apthorp, Bruno Vincenzi, Alexia Bertuzzi, Joan Brunet, Matteo Lambertini, Clara Maluquer, Paolo Pedrazzoli, Federica Biello, Alasdair Sinclair, Samira Bawany, Saira Khalique, Sabrina Rossi, Lucy Rogers, Cian Murphy, Katherine Belessiotis, M Carmen Carmona-García, Rachel Sharkey, David García-Illescas, Gianpiero Rizzo, Marta Perachino, Nadia Saoudi-Gonzalez, Kris Doonga, Laura Fox, Elisa Roldán, Gianluca Gaidano, Isabel Ruiz-Camps, Riccardo Bruna, Andrea Patriarca, Clara Martinez-Vila, Luca Cantini, Alberto Zambelli, Raffaele Giusti, Francesca Mazzoni, Enrico Caliman, Armando Santoro, Federica Grosso, Alessandro Parisi, Paola Queirolo, Avinash Aujayeb, Lorenza Rimassa, Aleix Prat, Marco Tucci, Michela Libertini, Salvatore Grisanti, Uma Mukherjee, Nikolaos Diamantis, Vittorio Fusco, Daniele Generali, Salvatore Provenzano, Alessandra Gennari, Josep Tabernero, Alessio Cortellini, Joanne S Evans, Judith Swallow, Chris Chung, Meera Patel, Gino Dettorre, Diego Ottaviani, Amani Chowdhury, Eve Merry, Neha Chopra, Alvin JX Lee, Christopher CT Sng, Tamara Yu, Marianne Shawe-Taylor, Hamish DC Bain, Yien Ning Sophia Wong, Myria Galazi, Sarah Benafif, Palma Dileo, Irina Earnshaw, Grisma Patel, Anjui Wu, Gehan Soosaipillai, Lee Cooper, Ramis Andaleeb, Saoirse Dolly, Eleanor Apthorp, Krishnie Srikandarajah, Eleanor Jones, Mieke Van Hemelrijck, Charlotte Moss, Beth Russell, John Chester, Angela Loizidou, Martine Piccart, Claudia A Cruz, Roxana Reyes, Elia Segui, Javier Marco-Hernández, Margarita Viladot, Simeon Eremiev, Roser Fort-Culillas, Isabel Garcia, Raquel Liñan, Ariadna Roqué Lloveras, Nadia Harbeck, Rachel Wuerstlein, Franziska Henze, Sven Mahner, Eudald Felip, Anna Pous, Francesca D'Avanzo, Lorenza Scotti, Marco Krengli, Andrea Marrari, Sara Delfanti, Antonio Maconi, Marta Betti, Giuseppe Tonini, Giuseppina Rita Di Fazio, Carlo Tondini, Lorenzo Chiudinelli, Michela Franchi, Michela Libertini, Rossella Bertulli, Alice Baggi, Valeria Tovazzi, Corrado Ficorella, Giampiero Porzio, Maristella Saponara, Marco Filetti, Federica Zoratto, Francesco Paoloni, Rossana Berardi, Annalisa Guida, Sergio Bracarda, Maria Iglesias, Ana Sanchez de Torre, Marco Tagliamento, Emeline Colomba, Fanny Pommeret
Journal: The Lancet Oncology (2022)
A retrospective study of ipilimumab plus nivolumab in anti–PD-L1/PD-1-refractory merkel cell carcinoma.
Authors: Sophia Z. Shalhout, Kevin S. Emerick, Howard E. Kaufman, David M. Miller
Journal: Journal of Clinical Oncology (2022)

9521 Background: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma with a high recurrence and mortality rate. Immune checkpoint inhibitors (ICIs) targeting the PD-L1/PD-1 axis have shown significant clinical benefit with durable responses in patients with advanced MCC leading to regulatory approvals by the U.S. Food and Drug Administration for two agents: avelumab (anti-PD-L1) and pembrolizumab (anti-PD-1). However, many patients (̃50%) with advanced MCC treated with ICI do not experience tumor regression. Studies regarding systemic therapy options following progression due to primary or acquired resistance to immunotherapy are limited and management remains a clinical challenge. In this retrospective study, we evaluated objective clinical response to combination ipilimumab and nivolumab (ipi-nivo) salvage therapy in advanced MCC refractory to anti-PD-L1/PD-1 treatment. Methods: We reviewed the electronic medical record at Mass General Brigham associated institutions to identify patients with advanced MCC that progressed on upfront immunotherapy (e.g., pembrolizumab, avelumab or nivolumab) and were re-challenged with combination ipi-nivo between 2016 to 2021. Patients treated with prior surgery, radiation, or cytotoxic chemotherapy after progressing on immunotherapy were not excluded. Responses to ipi-nivo were evaluated for every patient at each re-staging/interval assessment following baseline analysis utilizing Response Evaluation Criteria in Solid Tumors (RECISTv1.1) as well as immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) to ensure conventional RECIST did not underestimate the benefit of ipi-nivo. Results: Four patients (31%) experienced grade III/IV immune-related adverse events. No patients (0/13) in this case series achieved an objective response via RECISTv1.1/irRECIST. Stable disease was seen in 23% (3/13) and the median progression-free survival was 1.3 months (90% CI, 1.1-1.5). The median overall survival from the initiation of ipi-nivo was 4.7 months (95% CI, 3-17). Conclusions: This study suggests limited, if any, clinical benefit of ipi-nivo in patients with advanced anti-PD-L1/anti-PD-1-refractory MCC. New strategies for second-line treatment of MCC are needed and referral to innovative clinical trials should be a priority for patients with refractory metastatic MCC.
5-year outcomes of High-Intensity Focused Ultrasound (HIFU) treatment of localised prostate cancer
Authors: C. Deleuze, E. Barret, A. Fregeville, F. Rozet, P. Macek, Y. Barbe, C. Lainé, Q. Mandoorah, A. Mombet, N. Cathala-Mignon, X. Cathelineau
Journal: European Urology (2022)
What is the impact of ischemic heart disease on PSA testing?
Authors: John Panzone, Christopher Welch, Maximillian S Wu, Joseph M Jacob, Oleg Shapiro, Alina Basnet, Gennady Bratslavsky, Hanan Goldberg
Journal: Journal of Clinical Oncology (2022)

e17014 Background: Prostate Specific Antigen (PSA) testing can improve early prostate cancer detection. However, numerous factors can influence patients’ willingness and ability to undergo PSA testing. Methods: We performed a cross-sectional study investigating the impact of various degrees of ischemic heart disease (IHD) on PSA testing. We assessed 3,822 male respondents aged 55-75 from the 2018 year of the National Health Interview Survey (NHIS). Men were stratified according to the degree of IHD (none, history of angina pectoris (AP), history of myocardial infarction (MI), or history of neither, but with a diagnosis of IHD). Multivariable logistic regression analysis was used to assess the relationship between IHD and being tested for PSA, adjusting for known cofounders. Results: Multivariable logistic regression demonstrated that males with a history of IHD (no MI or AP) were more likely to have ever been PSA tested than males without IHD (p = 0.012, OR = 1.630, 95% CI 1.115-2.383), as seen in Table. Additionally, older age (p &lt; 0.001), having a partner (vs. no partner p &lt; 0.001), homosexual sexual orientation (vs. heterosexual orientation p = 0.007), and a history of cancer (vs. no history p &lt; 0.001) all increased likelihood of being PSA tested. In contrast, Asian race (vs. White, p = 0.001), and being a current smoker (vs. no smoking history, p &lt; 0.001) decreased the likelihood. Interestingly, males with a history of a symptomatic IHD (MI or AP) were not shown to be more likely to undergo PSA testing. Conclusions: Our results suggest that males with non-symptomatic IHD are more likely to be PSA tested. Males with symptomatic IHD do not seem to undergo more PSA screening, perhaps due to lower suggested life expectancy. Awareness of discrepancies in PSA testing in men with IHD should be raised. Table - Multivariable logistic regression analyses demonstrating relationships with likelihood of being PSA tested.[Table: see text]
Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?
Authors: Ignacio Ortego, Javier Molina-Cerrillo, Alvaro Pinto, Matteo Santoni, Teresa Alonso-Gordoa, M. Pilar Lopez Criado, Alejandro Gonzalez-Morales, Enrique Grande
Journal: Journal of Clinical Oncology (2022)

e16541 Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1 st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1 st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1 st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.
Adherence to genetic testing guidelines in pancreatic cancer and impact on treatment.
Authors: Fionnuala Crowley, Michelle Rudshteyn, Sonal Gandhi, Michael Wotman, Mantej Sehmbhi, Deirdre Jill Cohen
Journal: Journal of Clinical Oncology (2022)

e16238 Background: NCCN June 2019 Guidelines recommend that clinicians consider germline (GL) testing for patients(pts) diagnosed with pancreatic cancer (PDAC) and consider molecular analysis of tumors in pts with metastatic disease. Up to 25% of advanced PDAC pts have GL or somatic mutations in the DNA damage repair (DDR) pathway which are predictive of response to platinum chemotherapy (plat) and maintenance therapy with olaparib. Referral for genetic testing (GT) at our institution is currently made at provider discretion. We aimed to determine rates of GT, factors associated with GT, and outcomes of those tested. Methods: Frequency of GT testing was examined in pts with non-endocrine PDAC and &gt;2 visits between 6/2019 and 6/2021 at Mount Sinai Health System. Clinicopathological variables and treatment outcomes were also recorded. Results: 149 pts were included. 71 pts (48%) were male. 25 pts (17%) had a personal history of cancer and 8 (5.3%) with history of DDR related cancer (prostate, breast, ovarian). 66 pts (44%) had GL testing: 42 (28%) at diagnosis with the remainder later in treatment. The rate of GL testing increased every year: 33% (2019), 44% (2020), 61% (2021). There was no statistically significant association between decision to do GL testing and age, ECOG, race, personal or family history (FH) of cancer. A FH of DDR related cancer was positively associated with GL testing (47% vs 27% p=0.039). 8 pts (12% of pts tested) had pathological gMut: BRCA1 (1), BRCA2 (1), ATM (2), PALB2 (2) , NTHL1 (1), both CHEK2 and APC (1). 6 pts (75%) had GL testing at diagnosis. One g BRCA2 pt had a plat response. Neither g BRCA pt received a PARP inhibitor. 24 pts in total had a response to plat, 16 (67%) of whom had GL testing. 94 pts (63%) had molecular tumor testing (including 65% of pts with metastases). Pathogenic mut in DDR genes were identified in 9 pts: ARID1A (2), BRCA2 (3), ATM (2), PALB2 (2), CHEK2 (1). Four of these pts had corresponding gMuts. One pt with somatic ATM mut had g BRCA1 mut. Two pts with BRCA2 somatic mut did not have GL testing. Conclusions: GT based on provider discretion resulted in suboptimal rates of GL testing. However, since inception of national guidelines, testing rates nearly doubled. Rates of GL DDR mutations were lower than previously reported, with varying response to plat in this cohort. Future studies are needed to understand barriers to GT and improve implementation.[Table: see text]
GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy in patients with biliary tract cancers.
Authors: Wei Zhang, Dong Xiang, Chen Lu, Liu Chen, Tianqiang Song, Wei Lu
Journal: Journal of Clinical Oncology (2022)

e16133 Background: The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has made great progress recently in advanced biliary tract cancer (BTC). Multi-target TKI lenvatinib or next-generation sequencing (NGS)-guided molecular targeted therapy are also promising. The aim of this study was to explore the anti-tumor effects of combined GemOX plus anti-PD-1 sintilimab and TKI either by lenvatinib or by NGS-guided targeted therapy if there is available target for local advanced or metastatic BTCs. Methods: This is a prospective single arm clinical study. Patients with local advanced or metastatic BTC were given intravenous infusion of standard GemOX (85mg/m2 oxaliplatin on day 1 and gemcitabine 1000mg/m2 on a 1-8-day schedule of a 3-week treatment cycle) plus 200mg q3w of sintilimab and lenvatinib or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR mutation, lenvatinib for PDGFR and KIT mutation, lenvatinib for FGFR/KIT mutation). The primary end point was objective response rate (ORR), and the secondary end points were progression-free survival (PFS) and overall survival (OS). Tumor response was evaluated according to RECIST v1.1 criteria. Results: From November 2020 to December 2021, 22 patients with locally advanced or metastatic BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA) were enrolled in the regimen, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6 %). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. By December 31 st , 2021, the median follow-up time was 13.1 months. The most common adverse events were anorexia (68.2%), nausea (68.2%), vomiting (36.36%), hair loss (45.5%) and bone marrow suppression (63.6%). During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeting IDH2, EGFR, FGFR2, PDGFRA/KIT, BRCA2 and resulted in 1 SD and 4 PR with an ORR of 80% and DCR of 100%. The ORR and DCR were both 100% for 4 patients with programmed cell death ligand-1 (PD-L1) expression. While for the 3 patients with supper-progression markers such as RET, MDM2 and FGF14/STK24, there were 2 SD and 1 PD with an ORR of 0% and DCR of only 33%. Conclusions: In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.
GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease
Authors: Anja Baumann, Katharina Burger, Annette Brandt, Raphaela Staltner, Finn Jung, Dragana Rajcic, Maria Jose Lorenzo Pisarello, Ina Bergheim
Journal: Metabolism (2022)

Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved.Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662.Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2-) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2- formation.In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.
Targeting signaling pathways vulnerabilities for the treatment of IKZF1-deleted ph-negative B lymphoblastic leukemia.
Authors: Rohit Gupta, Jason H. Rogers, Xin Long, Rogelio Aguilar, Geraldo Medrano, Jaime Reyes, Michele Redell, Margaret A. Goodell, Rachel E. Rau
Journal: Journal of Clinical Oncology (2022)

7033 Background: Approximately 20% of children diagnosed with B lymphoblastic leukemia (B-ALL) will suffer a relapse, and most adults with B-ALL have a poor prognosis. Genome-wide association studies of B-ALL patients have identified frequent deletions of the gene IKZF1, encoding the master regulator of lymphoid development, IKAROS. These deletions are associated with therapy resistance, increased risk of relapse, and inferior survival. Currently, how loss of IKAROS function contributes to therapy resistance and increased risk of relapse is not fully understood. We used CRISPR-Cas9 genome editing to develop human B-ALL cell lines with various IKZF1 deletions that genetically and phenotypically recapitulate those occurring in patients. Using these isogenic cell lines, we have previously shown IKZF1 deletion results in cell-intrinsic chemoresistance and increased activation of the JAK/STAT signaling pathway (Rogers, Gupta et al. 2021). Methods: Given JAK/STAT is often dysregulated in poor-prognosis leukemia, we investigated the potential mechanisms of aberrant JAK/STAT activation and the therapeutic potential of targeting JAK/STAT in our engineered cell lines. We treated our cells with SH-4-54 (STAT3/5 inhibitor) or tofacitinib (JAK1 inhibitor) alone and in combination with dexamethasone. To elucidate how loss of IKAROS mediates an increase in JAK-STAT activity, we also performed RNAseq of known pathway regulators, comparing IKZF1 wild-type with IKZF1 knockout. Results: The JAK/STAT negative regulator Suppressor of Cytokine Signaling 2 (SOCS2) was significantly downregulated with IKZF1 deletion, validated by RTqPCR and immunoblotting. We further analyzed publicly-available RNAseq data from &gt; 650 pediatric B-ALL samples, finding that SOCS2 expression is significantly lower in patients with low IKZF1expression (likely corresponding to IKZF1 deletion) compared to those with high IKZF1 expression. When we treated our engineered cell lines with tofacitinib or SH-4-54, IKZF1 wild-type cells were sensitive to each compound, suggesting JAK/STAT signaling plays a vital role in cell survival. In contrast, the IKZF1-deleted cells were relatively resistant to JAK/STAT inhibitors alone. However, in combination with dexamethasone, treatment of cells with sub-IC50 levels of SH-4-54 or tofacitinib resulted in re-sensitization to glucocorticoid-induced apoptosis. Conclusions: Our findings support that IKZF1 deletion leads to a targetable upregulation of the JAK/STAT pathway that, when inhibited, results in relative re-sensitization to dexamethasone. JAK/STAT pathway upregulation in IKZF1 deleted cells may be mediated by decreased expression of SOCS2. These results provide initial promise for targeting these vulnerabilities for the treatment of this poor-prognosis disease.
Genomic insights into the recent chromosome reduction of autopolyploid sugarcane Saccharum spontaneum
Authors: Qing Zhang, Yiying Qi, Haoran Pan, Haibao Tang, Gang Wang, Xiuting Hua, Yongjun Wang, Lianyu Lin, Zhen Li, Yihan Li, Fan Yu, Zehuai Yu, Yongji Huang, Tianyou Wang, Panpan Ma, Meijie Dou, Zongyi Sun, Yibin Wang, Hengbo Wang, Xingtan Zhang, Wei Yao, Yuntong Wang, Xinlong Liu, Maojun Wang, Jianping Wang, Zuhu Deng, Jingsheng Xu, Qinghui Yang, ZhongJian Liu, Baoshan Chen, Muqing Zhang, Ray Ming, Jisen Zhang
Journal: Nature Genetics (2022)